Heart failure is a major cause of death throughout the world. In Japan, heart failure is one of the three major causes of death. A worldwide standard guideline for treating heart failure is to inhibit the chronically enhanced sympathetic nervous system activity in heart failure patients and renin-angiotensin system inhibitors and β-adrenoreceptor antagonists (β-blockers) are used as main therapeutics. However, transient inhibition of cardiac function by β-blockers is a big obstacle to introduction of the treatment for patients, especially for aged patients. On the other hand, β-blockers also have an inhibitory action on the respiratory tract and this causes a serious problem in aged patients who often have complications such as pulmonary emphysema. β-adrenoreceptors modulate cardiac function by increasing the concentration of intracellular cyclic AMP (cAMP) through activation of adenylyl cyclase enzyme present in the cell membrane. Briefly, the above-mentioned β-blockers exert their pharmacological effects by inhibiting the activity of adenylyl cyclase enzyme and the downstream cAMP signals. On the other hand, since β-adrenoreceptors are also expressed in the pulmonary bronchus, β-blockers cause bronchial smooth muscle contraction, which induces abnormalities in respiratory function.
Such adverse effects of β-blockers on the respiratory system may be explained by the fact that having only 3 subtypes, β-adrenoreceptors are relatively low in the organ specificity of their expression. On the other hand, adenylyl cyclase is known to have 9 subtypes and the subtypes called cardiac are expressed specifically in the heart but little in the lung. β-blockers classified as agents of class II in Vaughan Williams classification have long been known to have an anti-arrhythmic action. Therefore, by selectively inhibiting cardiac adenylyl cyclase, therapeutic effects on heart failure and arrhythmia which are similar to the effects of β-blockers might be exerted without causing adverse effects on the respiratory tract.
Some drugs targeting cardiac adenylyl cyclase have already been applied clinically (Non-Patent Document No. 1). Although some compounds have already been reported as cardiac adenylyl cyclase inhibitors (Non-Patent Documents Nos. 2 and 3), neither clinical application has started nor novel compounds have been reported. Animal experiments performed to date have strongly suggested that cardiac adenylyl cyclase inhibitors are potentially useful as therapeutics for heart failure (Non-Patent Documents Nos. 4 to 7).